Improvement of the Treatment of Loop Structures in the UNRES Force Field by Inclusion of Coupling between Backbone- and Side-Chain-Local Conformational States

Abstract

The UNited RESidue (UNRES) coarse-grained model of polypeptide chains, developed in our laboratory, enables us to carry out millisecond-scale molecular-dynamics simulations of large proteins effectively. It performs well in ab initio predictions of protein structure, as demonstrated in the last Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP10). However, the resolution of the simulated structure is too coarse, especially in loop regions, which results from insufficient specificity of the model of local interactions. To improve the representation of local interactions, in this work we introduced new side-chain-backbone correlation potentials, derived from a statistical analysis of loop regions of 4585 proteins. To obtain sufficient statistics, we reduced the set of amino-acid-residue types to five groups, derived in our earlier work on structurally optimized reduced alphabets, based on a statistical analysis of the properties of amino-acid structures. The new correlation potentials are expressed as one-dimensional Fourier series in the virtual-bond-dihedral angles involving side-chain centroids. The weight of these new terms was determined by a trial-and-error method, in which Multiplexed Replica Exchange Molecular Dynamics (MREMD) simulations were run on selected test proteins. The best average root-mean-square deviations (RMSDs) of the calculated structures from the experimental structures below the folding-transition temperatures were obtained with the weight of the new side-chain-backbone correlation potentials equal to 0.57. The resulting conformational ensembles were analyzed in detail by using the Weighted Histogram Analysis Method (WHAM) and Ward's minimum-variance clustering. This analysis showed that the RMSDs from the experimental structures dropped by 0.5 Å on average, compared to simulations without the new terms, and the deviation of individual residues in the loop region of the computed structures from their counterparts in the experimental structures (after optimum superposition of the calculated and experimental structure) decreased by up to 8 Å. Consequently, the new terms improve the representation of local structure.

Performance of protein-structure predictions with the physics-based UNRES force field in CASP11

“…UNRES force field managed to achieve comparable results to the most of the TBM methods also for other 'FM' targets and domains, such as T0763-D1, T0771-D1, T0775-D2, T0793-D2, T0820-D1 and T0834-D2. It is also remarkable that, in CASP11, there is only a small difference between the ranking of our 'model 1's' and our best models indicating that the UNRES force field, supplemented with the recently introduced terms corresponding to the coupling of the backboneand side-chain-local interactions (Krupa et al, 2013;Sieradzan et al, 2015), enables us to select the most native-like predictions out of the five models more accurately than the previous version of the force field used in CASP10. The better overall performance of our approach in CASP11 compared with previous CASP exercises was achieved because of recent addition of the new potentials coupling the backbone-local and sidechain-local conformational states.…”

“…U ssbond is the disulfide bond formation potential calculated over all possible permutations of disulfide bonds (nss). The U SCÀcorr terms are new knowledge-and physics-based side-chain backbone correlation potentials (Krupa et al, 2013;Sieradzan et al, 2015) recently introduced to the UNRES force field, which improved the correctness of secondary-structure and loop modeling with the UNRES force field.…”

“…These targets represented all structural classes. We used the newest version of the UNRES force field supplemented with energy terms corresponding to the coupling between backbone-local and sidechainlocal conformational states (Krupa et al, 2013;Sieradzan et al, 2015).…”

Prediction of Protein Structure by Template-Based Modeling Combined with the UNRES Force Field

“…28,29 The terms U b and U rot are the virtual-angle bending and side-chain rotamer potentials, respectively, and the term U bond accounts for backbone and side-chain virtual-bond stretching; 4,30 recently, 31 we extended the backbone virtual-bond stretching term to account for the trans−cis transition of peptide groups. The terms U corr (m) and U turn (m) correspond to the correlations (of order m) between peptide-group electrostatic and backbone local interactions; 21,22 the terms U turn (m) (the "turn" terms) involve consecutive segments of the chain.…”

Common functionally important motions of the nucleotide‐binding domain of Hsp70

“…3 The SBD-closed (ADP-bound) structure of the DnaK Hsp70 chaperone from E. coli was determined by Zuiderweg and coworkers 10 by NMR spectroscopy (PDB: 2KHO). Recently, 11 we carried out molecular dynamics simulations, using the coarse-grained UNRES force field 12-15 developed in our laboratory, of the conformational transition of DnaK, starting from the SBD-closed 2KHO structure. We determined a probable structure of the SBD-open conformation 11 , which was unknown at the time, and which turned out to be very close to the x-ray structure of the SBD-open (ATP-bound) form of DnaK, which was determined by Mayer and coworkers 3 after the results of our simulations had been published.…”